The present invention relates to carrying out organic chemistry on solid supports comprising derivatised functionalities, methods for synthesising said supports, methods for synthesising compounds comprising amine groups or N-containing heterocycles using said solid supports, intermediate compounds linked to said supports and uses therefor. In particular, the invention relates to solid supports comprising derivatised amide or sulphone groups, methods for synthesising said supports, methods for synthesising compounds comprising tertiary amine groups or N-containing heterocyclic compounds using said supports and intermediate compounds comprising quaternary ammonium groups linked to said supports and uses therefor.
Solid phase chemistry is well known in the art, particularly in the fields of peptide and oligonucleotide synthesis. Advantages associated with solid phase synthesis include the ability to drive reactions to completion by use of excess reagents, ease of work up and potential automation of synthetic procedures. Organic compounds have traditionally been attached to the solid support by certain cleavable linker groups which yield, on cleavage, compounds in which polar functionality remains at the point of attachment, for example a CO2H, OH, NH2, CONH2 or a CONHR group. The synthesis of non-oligomeric organic compounds using resin-bound synthetic routes is a key component of the emerging technology of combinatorial chemistry (Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385-1401; Lowe, G. Acc. Chem. Res. 1995, 24, 309-317; Fruchtel, J. S.; Jung, G. Angew. Chem. Int. Ed. Engl. 1996, 35, 17-42).
One of the current limitations of this approach is the requirement for a xe2x80x9chandlexe2x80x9d to link small organic molecules onto a polymeric resin. In Merrifield peptide synthesis, for example, a carboxylic acid is linked via an ester group. Recently the range of linkers has increased (Fruchtel, J. S., and Jung G. supra).
Morphy J. R. et al. Tetrahedron Letters, 1996, 37, 3209-3212 report a novel linker strategy and describe a new type of linker and release system for resin-bound synthesis which is based upon Michael addition and Hofmann elimination (xcex2-elimination) reactions. The synthetic route is outlined in the following Scheme below: 
where R1, R2 R3each represent an alkyl group and X is Br or I. Where 3a is a secondary amine (R2=H), conversion to a tertiary amine is achieved by reductive alkylation on the resin using a suitable aldehyde and NaBH(OAc)3 in 1% acetic acid/dimethylformamide for 18 hours at 20xc2x0 C.
The outlined synthetic route above utilises hydroxymethyl polystyrene resin derivatised with acryloylchloride to the acrylate ester 1. Michael addition of a secondary amine 2 gives the resin-bound tertiary amine 3. Alternatively, a primary amine 2 (R2=H) gives a resin-bound secondary amine which is converted into the tertiary amine 3 (R2=alkyl) by reductive alkylation. Quaternisation of the tertiary amine 3 with an alkyl halide 4 to give 5 introduces another site of diversity and activates the linker for cleavage by a facile Hofmann elimination reaction. Thus iPr2NEt (diisopropylethylamine; DIEA) at room temperature liberates the tertiary amine 6 into solution and regenerates the resin 1.
Since the resin linker 1 is regenerated after cleavage of the product and is functionalised via a Michael reaction, the resin is referred to as a REM resin (Morphy, supra).
A disadvantage of the above outlined reaction is that the ester derivatised resin, in this case originating from an acrylate ester, can be unstable under certain reaction conditions such as strong acid, strong base, or others reaction conditions including reagents such as Grignard reagents, and reducing agents such as LiAlH4 and the like. In such reaction conditions, cleavage at the ester bond may occur. Thus, the general applicability of the ester derivatised resin can be limited. and as a consequence, the solid phase synthesis of desired amine-containing compounds or N-containing heterocyclic compounds may not be realised.
The present invention seeks to mitigate against the disadvantages associated with the prior art and to provide derivatised solid supports which are stable to a wide range of chemistries and whereon a broad scope of amines or N-heterocyclic containing compounds can be prepared utilising the Hoffmann elimination reaction, as described above, to release the amines from the solid supports.
According to a first variant of the invention there is provided a solid support comprising a functionalised amide according to Formula (I). 
wherein 
represents the solid support;
B is a conventional spacer arm or a bond;
R is selected from H, (C1-C6)alkyl, optionally substituted with halogen. aryl(C1-C6)alkyl and aryl, optionally substituted with (C1-C6)alkoxy, OH or halogen;
W is selected from O and S;
Y is CHR4 where R4 is selected from H, (C1-C4)alkyl, optionally substituted with halogen, and phenyl, optionally substituted with CF3, (C1-C6)alkoxy;
Z is CR5R6xe2x80x94L where R5 and R6 are independently selected from H, (C1-C4)-alkyl, and phenyl; L is a leaving group; or
Y and Z together form CR4xe2x95x90CR5R6 wherein R4 and R5 are as defined above, or wherein R4 and R5 together with the carbon atoms to which they are bonded form a (C4-C8)cycloalkene ring.
The term (C1-C6)-alkyl as used in the definition of formula I means a straight or branched-chain alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl and hexyl.
The term (C1-C4)alkyl means, likewise, a straight or branched-chain alkyl group having 1-4 carbon atoms.
The term (C1-C6)alkoxy means a (C1-C6)alkyloxy group, wherein (C1-C6)alkyl has the previously given meaning. A preferred (C1-C6)alkoxy group is methoxy. Preferred (C1-C6)alkoxy substituted aryl groups are 2-methoxyphenyl and 4-methoxyphenyl.
The term halogen means F, Cl, Br or I.
The term aryl means an aromatic ring system having from 6-12 carbon atoms, such as for example phenyl and naphthyl; a preferred aryl group is phenyl.
The term aryl(C1-C6)alkyl as used in the definition of formula I means an aryl group, having the meaning as previously defined, linked to a (C1-C6)alkyl group as previously defined, such as benzyl (phenylmethyl).
The term (C4-C8)cycloalkene ring, as used in the definition of formula I means a cycloalkene ring having 4-8 carbon atoms, like cyclobutene, cycloheptene, cyclohexene, cycloheptene and cyclooctene.
The term leaving group is known in the art of substitution reactions (Advanced Org. Chem (1992) (4th Ed.) March J, p 352, Wiley and Sons). Examples of well known leaving groups are Cl, Br, I, tosyloxy, mesyloxy, trifluoromethanesulphonyloxy, trifluoroethanesulphonyloxy (tresyloxy) and the like.
The conventional spacer arm B, as used in the definition of Formula I, means a chemical structure linking (or interspaced between) a functional group to the backbone structure of the solid support. B may be any conventional spacer arm commonly employed in solid phase organic chemistry. For instance, the spacer arm B of a chloromethylated or an aminomethylated polystyrene divinylbenzene (Merrifield) resin, is the methylene, xe2x80x94CH2xe2x80x94 group. Further examples of spacer arms B are (CH2)n, CH2(OCH2CH2)n wherein n=0, 1, 2, 3 or 4, CH2C(CH3)(PEG)2, PEG (polyethyleneglycol)-CH2 and the like. Examples of these and other suitable spacer arms can be found in The Combinatorial Chemistry Catalog, February 1997 (NovaBiochem) pp1-37.
In a preferred embodiment of the first main aspect of the invention, B is selected from (CH2)n and CH2(OCH2CH2)n and n is 0, 1 or 2; R is selected from H, (C1-C4)alkyl and phenyl; W is O; and Y and Z together form CR4xe2x95x90CR5R6 wherein R4, R5 and R6 are independently selected from H, CH3 and phenyl; or Y is CHR4 where R4 is selected from H, CH3 and phenyl and Z is CR5R6xe2x80x94L where L is a leaving group selected from Br, Cl, I, tosyloxy, mesyloxy and trifluoromethanesulphonyloxy.
In a further preferred embodiment, B is CH2; R is selected from H, CH3, C2H5, C3H7 (ie straight or branched-chain), and phenyl; W is O; and Y and Z together form CHxe2x95x90CH2 or Y is CH2 and Z is CH2xe2x80x94L where L is a leaving group selected from Br, Cl, I, tosyloxy, mesyloxy, and trifluoromethanesulphonyloxy.
In a particular preferred embodiment B is CH2; R is H; W is O; Yxe2x80x94Z is CHxe2x95x90CH2, and the solid support is the polystyrenedivinylbenzene support of a Merrifield resin.
The selection of a solid support may be made from conventional commercially available solid support materials such as resins, for example, aminomethyl polystyrene and the like. Other suitable solid support resins for use in the present invention can be found in, for example, The Combinatorial Chemistry Catalog, supra. Suitable solid supports include polystyrene optionally cross-linked with a cross-linking agent such as divinyl-benzene, acrylamides such as polyacrylamide, dimethylacrylamide, and polystyrene acrylamide, glass, silica gels, polyethylene glycol (PEG), polyethylene glycol-polystyrene (PEG-PS) resin, ARGOGEL(trademark) (Argonaut Tech. Inc.), cellulose, pore-glass, for example, is the form of pore-glass, beads, latex, and macroporous supports and the like.
The solid support as used in the invention may be in various physical forms, such as in the form of beads, the most commonly used polystyrene based resins (The Combinatorial Chemistry Catalog, vide supra), pins, such as polypropylene/polyethylene pins and the like; pellets; disks; capillaries; hollow or solid fibres. The solid support may be flat, or alternatively; or other shaped may be in the form of substantially spherical; beads, such as a polygonal shape, for example a hexagon.
The person skilled in the art will appreciate that the selection of a solid support will depend on the reaction conditions employed and/or envisaged in the synthesis of desired amines or N-heterocyclic containing compounds. Supports may be selected as appropriate with a view to such factors as the mildness or harshness of the reaction conditions employed. Macroporous solid supports can be viewed as those types wherein the structure remains substantially permanently swollen, irrespective of the choice of solvent. For example, those containing as the base material. polystyrene, styrene-divinylbenzene copolymer, glass, silica gel, polypropylene, polyvinyl alcohol, poly(2-hydroxyethyl methacrylate), oligo(ethyleneglycol) dimethacrylate polymer, polyacrylamide and Kiesel-guhr. Preferred supports include polystyrene cross-linked to varying degrees with divinylbenzene to give either a microporous or macroporous support, polyethyleneglycol (PEG) or PEG-derivatised polystyrene. Such supports may either be in the form of supports functionalised with appropriate groups such as NHR or functionalised with groups which may be converted to such NHR groups. The selection of solid support is not critical provided that it comprises appropriate NHR groups or is a solid support comprising groups capable of being functionalised to NHR groups. Such supports are known to the person skilled in the art, such as those made by converting a chloromethylated polystyrene resin to an amino functionalised resin via an appropriate alkylation reaction.
Generally, an amide-functionalised support of Formula (I) can be prepared from a suitable solid support such as a resin comprising an amine group, of Formula (II): 
where B and R are as defined hereinabove, by acylation with a suitably activated acid derivative according to formula Yxe2x80x94Zxe2x80x94COOH, wherein Y and Z are as defined above, such as an activated ester derivative or an acid chloride derivative, after which the resulting amide may be optionally converted to a thioamide, for instance, by treatment with phosphorous pentasulfide. For instance, an amide functionalised support of Formula I can be prepared from a suitable so. support of Formula II by the addition of a suitable carbonyl chloride, such as an acid chloride, for example, acryloyl chloride or 3-bromopropionoyl chloride, under suitable reaction conditions, for example, in the presence of a tertiary amine base, such as diisopropyl ethyl amine (DIEA) in a suitable organic solvent, such as dichloromethane. Such reaction conditions are familiar to the man skilled in the art.
In a second aspect of the invention, there is provided a process for the preparation of a tertiary amine which comprises:
(i) adding a primary or secondary amine to an amide-functionalised support according to Formula (I) by way of a Michael addition to an unsaturated amide or by alkylating a propionamide having a leaving group L in the 3 position:
(ii) adding an alkylating agent to the product of step (i); and
(iii) performing a Hofmann elimination on the quaternary ammonium compound generated in step (ii).
In a variant of the second aspect of the invention there is provided a process for the preparation of a tertiary amine which comprises:
(i) adding a primary amine to an amide-functionalised support according to Formula (I) by way of a Michael addition to an unsaturated amide or by alkylating a propionamide having a leaving group L in the 3 position;
(ii) performing a reductive alkylation on the secondary amine produced in step (i) giving a tertiary amine;
(iii) adding an alkylating agent to the product of step (ii); and
(iv) performing a Hofmann elimination on the quaternary ammonium compound generated in step (iii).
Reference is made to the outline reaction Scheme 1, below: 
The primary or secondary amine HNR7R8 may be any primary or secondary amine capable of undergoing a Michael addition to the amide-functionalised resin giving 3 (Route A).
R7 and R8 may be selected from H, branched or straight chain (C1-C6)alkyl such as methyl, ethyl, propyl, isopropyl, butyl, and sec.butyl, (C1-C6)alkyl ethers such as methyloxyethyl, arylalkyl such as phenylethyl, (C1-C6)alkyl-Oxe2x80x94(C1-C6)alkylene, vinyl (C1-C6) alkylene, such as allyl and the like.
Alternatively, R7 and R8 may form part of a ring structure, for example, in secondary amines such as ethyl isonipecotate (ethyl 4-piperidinecarboxylate), 4-benzyl piperidine, piperazine such as 1-phenyl piperazine, 1,2,3,4-tetrahydroisoquinoline, and proline. In general, the secondary amine can be any secondary amine which can be employed in a Michael addition reaction leading to compound 3.
The alkylating agent may be any alkylating agent such as an alkylating agent of the formula R9X, where X is selected from I, Br, Cl, trifluoromethanesulphonyloxy, and R9 is an alkyl group which can be added to compound 3 in the synthesis of the quaternary compound 5. Suitable R9 alkyl groups include branched or straight chain (C1-C6)alkyl such as methyl, ethyl, propyl, n-butyl, (C1-C6)alkyl ethers such as methyloxyethyl, arylalkyl such as phenylmethyl, (C1-C6)alkyl-Oxe2x80x94(C1-C6)alkylene, vinyl(C1-C6)alkylene, such as allyl and the like. The person skilled in the art will appreciate that generally the selection of R7, R8 and R9 is such that the groups are ones which are capable of being utilised in the generation of tertiary amines in the solid phase syntheses described herein. When selecting R7 and R8 groups when these relate to branched chain substituents, the skilled addressee will appreciate that a branch point comprising a quaternary carbon will not be located on an atom adjacent to the N.
It will be appreciated that, in addition to the three characteristic steps of the methodology (Michael addition, quaternisation, Hofmann), it is possible to add extra steps to elaborate the structure of the bound compound (for example, structure 3 of Scheme 1; structure 3 of Scheme 4) and thereby expand the diversity of a combinatorial library or array. As such, the man skilled in the art will also appreciate that the solid supports of the invention may be adapted for use in peptide synthesis, oligonucleotide synthesis and the like.
For example, an amine R7R8NH may be added to the resin, then R8 may be elaborated to R10, for example, via an addition or displacement reaction such as described by Hermkens P. H. H. et al. Tetrahedron 53 5643-5678, 1997. Quaternisation with an R9X and base catalysed cleavage may then provide an elaborated amine NR7R9R10 as outlined in scheme 2 below. A specific example would be the addition of ethyl isonipecotate to the resin, then addition of MeMgBr, quaternisation with methyl iodide, and cleavage with DIEA, giving compound (2) (see Scheme 2 below). 
The person skilled in the art will appreciate that if one of the R groups (ie R7, R8 or R9) is removed subsequent to cleavage of the tertiary amine from the resin, a secondary amine will result. An example of a removable group could be p-methoxybenzyl, cleavable under acidic conditions such as TFA. In a variant of the second aspect of the invention a primary amine (instead of a secondary amine) may be used in step (i), giving rise to a secondary amine which may be converted to a tertiary amine by the introduction of a reductive alkylation step under appropriate reaction conditions, prior to the addition of the alkylating agent, such as R9X, of step (ii).
In the case where the amide functionalised support takes the form: 
B, R, W, R4, R5, R6, and L are as defined hereinbefore. Examples of suitable resin derivatives of Formula (III) are as hereinbefore described.
The man skilled in the art will appreciate that the amide functionalised resin of Formula (III) may participate in an alkylation reaction with an appropriate primary or secondary amine to form a compound 3 as per the general description given hereinabove (Route B, Scheme 1).
In a third aspect of the invention there is provided as an intermediate in the obtaining of a tertiary amine a quaternary ammonium compound linked to a support according to the following Formula (IV): 
wherein B, R, W, R4, R5, R6, R7, R8, and R9 are as defined hereinabove, and Xxe2x88x92 is a counteranion, such as Brxe2x88x92, Ixe2x88x92, or an acid derived anion.
In a preferred embodiment B is selected from (CH2)n and CH2(OCH2CH2)n; n is 0, 1 or 2; R is selected from H, (C1-C4) alkyl, and phenyl; W is O; and R4, R5 and R6 are H. In a further preferred embodiment B is CH2; R is selected from H, CH3, C2H5, C3H7 (ie straight or branched chain), and phenyl; W is O; and R4, R5 and R6 are H. In a still further preferred embodiment B is CH2; R is H; and R4 R5 and R6 are H.
In a fourth aspect of the invention, there is provided use of an amide functionalised support according to any one of Formulae (I), (III) or (IV) in the synthesis of a tertiary amine, or in the synthesis of N-containing heterocyclic compounds capable of quaternisation.
In a fifth aspect of the invention, there is provided, the use of an amide functionalised support according to any one of Formulae (I), (III), or (IV) in the manufacture of a combinatorial chemistry library or array of compounds.
In a second variant of the invention there is provided a sulphone functionalised solid support of Formula (V). 
wherein 
represents the solid support;
B is a conventional spacer arm or a bond;
C is O, NR, S, CH2 or SO2;
R is selected from H, (C1-C6)alkyl, optionally substituted with halogen, aryl(C1-C6)alkyl and aryl, optionally substituted with (C1-C6)alkoxy, OH or halogen;
b is an integer selected from 0 and 1;
D is selected from (C1-C6)alkylene, arylene, optionally substituted with halogen, and arylene(C1-C6)alkylene: or D is absent;
Y is CHR4 where R4 is selected from H, (C1-C4)alkyl, optionally substituted with halogen, and phenyl, optionally substituted with CF3, (C1-C6)alkoxy;
Z is CR5R6xe2x80x94L where R5 and R6 are independently selected from H, (C1-C4)-alkyl, and phenyl; L is a leaving group; or
Y and Z together form CR4xe2x95x90CR5R6 wherein R4 and R5 are as defined above, or wherein R4 and R5 together with the carbon atoms to which they are bonded form a (C4-C8)cycloalkene ring;
with the proviso that when D is absent C is not SO2, S or O, and when D is xe2x80x94CH2xe2x80x94, C is not SO2.
The term (C1-C6)alkylene as used in the definition of formula V means a bivalent radical having 1-6 carbon atoms, such as methylene, ethylene, trimethylene, 1 -methylethylene, tetramethylene, pentamethylene, hexamethylene. A preferred (C1-C6)alkylene group is methylene.
The term arylene means a bivalent aromatic radical of an aromatic ring system having from 6-12 carbon atoms, such as for example 1,2-phenylene, 1,3-phenylene, 1,4-phenylene or 1,4-naphthalenediyl; a preferred arylene group is 1,3-phenylene. The remaining terms in the definition of formula V have the meaning as previously given.
Preferred solid supports as used in the sulphone functionalised solid support of Formula (V) include polystyrene based resins. cross-linked to varying degrees with divinylbenzene to give either a microporous or macroporous support, polyethyleneglycol (PEG) or PEG-derivatised polystyrene.
In a preferred embodiment, B is selected from (CH2)n, CH2(OCH2CH2)n, xe2x80x94CH2C(CH3)(PEG)2 and PEGxe2x80x94CH2; n is 1 or 2; C is O or is absent; D is phenylene or is absent; and Y and Z together form CR4xe2x95x90CR5R6 wherein R4, R5 and R6 are independently selected from H, CH3 and phenyl; or Y is CHR4 and Z is CR5R6xe2x80x94L where R4, R5 and R6 are independently selected from H, (C1-C4)alkyl, and phenyl; and L is a leaving group; with the proviso that when D is absent C is not O.
In a further preferred embodiment B is CH2; C is O and D is 1,3-phenylene; or C and D are absent: Yxe2x80x94Z are xe2x80x94CHxe2x95x90CH2; or Y is CH2 and Z is CH2xe2x80x94L where L is a leaving group; and the solid support is the polystyrenedivinylbenzene support of a Merrifield resin.
In a particular preferred embodiment B is CH2; C is O and D is 1,3-phenylene; Y is CH2 and Z is CH2xe2x80x94L where L is Cl; and the solid support is the polystyrenedivinylbenzene support of a Merrifield resin.
Upon attachment of a primary or secondary amine (HNR7R8; derivatives 3 in Scheme 4) to this preferred sulphone functionalised solid support, the derivatised support was found (i) to be stable to alkoxides (e.g. sodium methoxide at room temperature), allowing, for example, transesterification reactions (such as the conversion of ethyl ester into methyl esters), and (ii) to be stable to Grignard reagents (e.g. phenylmagnesium bromide at room temperature), allowing, for example, resin bound esters to be converted to alcohols.
Amine derivatives (derivatives 3 in Scheme 4) prepared from another preferred sulphone functionalised Merrifield derived support according to formula V wherein B is CH2, C and D are absent and Xxe2x80x94Y represents CH2xe2x80x94CH2, were found, in addition to being stable to alkoxides and Grignard reagents, to be stable (iii) to strong acids (e.g. 6M HCl in dioxane at reflux) allowing, for example, cyclic ketals to be converted into ketones, to be stable to (iv) nucleophilic hydride reducing agents (e.g. sodium borohydride at room temperature) allowing, for example, imines to be converted to amines, and to be stable (v) to electrophilic hydride reducing agents (e.g. diborane-DMS complex at room temperature) allowing, for example, amides to be converted into amines.
The stability advantages mentioned for the sulphone functionalised supports of the invention in comparison with the prior art REM resins (Morphy et al. supra) allow a much wider range of chemical reactions to be carried out on the supports, and consequently increases the diversity of compound libraries which can be made using the supports of the invention.
Generally, a sulphone-functionalised support of Formula (V) can be prepared from a suitable solid support such as a resin comprising a leaving group, for example a resin of Formula (VI) 
where (B) and L are as defined hereinabove. The solid support (VI) may be thiolated with a thiol compound of formula:
xe2x80x83HSxe2x80x94Yxe2x80x94Zxe2x80x94OH
wherein Y and Z are as defined herein. The resulting thioether alcohol may then be oxidised to a sulphone alcohol, followed by substitution of the OH group with an activating group (a leaving group L) such as Br, Cl, tosyloxy, mesyloxy, or trifluoromethanesulphonyloxy. Alternatively, compounds of Formula (V), wherein C is NR and D is absent, can be prepared by acylation of an amine-functionalised solid support with a sulphonyl chloride according to general formula Lxe2x80x94Zxe2x80x94Yxe2x80x94SO2xe2x80x94Cl wherein L, Y and Z are as defined herein. Synthesis of a support according to formula V can be illustrated with reference to Scheme 3 where HSxe2x80x94Yxe2x80x94Zxe2x80x94OH is mercaptoethanol, and a representative resin of Formula (VI) is Merrifield resin (a chloromethylated polystyrene resin) available from Novobiochem: 
[(i) 10 eq. mercaptoethanol/Cs2CO3, DMF, 20xc2x0 C., 3 d.;(ii) excess m-CPBA, DCM, 20xc2x0 C., 12 h (or excess Oxone, aq. DMF, 20xc2x0 C., 12 h); (iii) PBr3, DCM, 20xc2x0 C., 16-24 h (or 10 eq. Mesyl Cl. DCM, 20xc2x0 C., 2 hr.)]; 
Reference is made to Scheme 4. 2xe2x80x2-Bromoethyl- and 2xe2x80x2-mesyloxyethyl sulfones 2 (L=Br or OMs) can be used as masked forms of a vinyl sulfone 6 in several reactions with secondary amines, such as tetrahydroiso-quinoline (THIQ), piperidines, morpholine, pyrolidine and dioctylamine and the like to give resin-bound tertiary amine products 3 (Route B). After washing, the resin bound tertiary amine products can be treated with an alkylating agent such as allyl bromide, to give quaternised ammonium salts 4, and these may then be treated with DIEA to effect Hofmann elimination and release tertiary amines 5 (as HBr salts) from the resin. As in the amide-functionalised synthesis of tertiary amines, it can be seen that compounds 6 can be recycled by re-reacting with more secondary amine (Route A).
Reference is again made to Scheme 4
In an alternative, an amine 8 may then be added to an appropriate resin of choice, such as hydroxymethyl polystyrene 7 to give 3. Alkylation of 3 provides 4 followed by a cleavage reaction giving 6. 6 may then undergo addition of secondary amine giving 3 followed by alkylation andxe2x80x94elimination generating a tertiary amine or N-containing heterocyclic compound with concomitant re-generation of the vinyl sulphone functionalised support.
In a further aspect of the invention there is provided a process for the preparation of a tertiary amine or an N-containing heterocyclic compound which comprises:
(i) adding a primary or secondary amine to a sulphone-functionalised support according to Formula (V) by way of a Michael addition to a vinyl sulphone or by alkylation using an ethyl sulphone having a leaving group in the 3 position forming a tertiary amine;
(ii) adding an alkylating agent forming a quaternary ammonium compound;
(iii) performing a Hofmann elimination on the quaternary ammonium compound generated in step (ii).
In a variant of the above aspect of the invention there is provided a process for the preparation of a tertiary amine which comprises:
(i) adding a primary amine to a sulphone-functionalised support according to Formula (V) by way of a Michael addition to a vinyl sulphone or by alkylation using an ethyl sulphone having a leaving group in the 3 position;
(ii) performing a reduction alkylation on the secondary amine produced in step (i) giving a tertiary amine;
(iii) adding an alkylating agent to the product of step (ii); and
(iv) performing a Hofmann elimination on the quaternary ammonium compound generated in step (iii).
In a third aspect of the invention there is provided as an intermediate in the obtaining of a tertiary amine a quaternary ammonium compound linked to a support according to the Formula (VII): 
wherein B, C, D, R4, R5, R6 R7, R8, R9, and b are as defined hereinabove, and Xxe2x88x92 is a counteranion, such as Brxe2x88x92, Ixe2x88x92, or an acid derived anion.
B may be any conventional spacer such as (CH2)n, CH2(OCH2CH2)n, PEG-CH2, and xe2x80x94CH2C(CH3)(PEG)2; and n is 0, 1, 2, 3 or 4.
In a preferred embodiment B is selected from (CH2)n, CH2xe2x80x94(OCH2CH2)n, CH2C(CH3)(PEG)2, and PEG-CH2; n is 1 or 2; C is O or is absent; D is phenylene or is absent; and R4, R5 and R6 are independently selected from H, (C1-C4)alkyl, and phenyl: with the proviso that when D is absent C is not O. In a further preferment, B is CH2; C is O and D is phenylene or C and D are absent; and CHR4xe2x80x94CR5R6 is CH2xe2x80x94CH2.
In another aspect of the invention there is provided use of a sulphone-functionalised support according to Formulae (V) or (VII) in the synthesis of a tertiary amine or in the synthesis of an N-containing heterocycle capable of quaternisation.
In a still further aspect of the invention, there is provided use of a sulphone-functionalised support according to Formulae (V) or (VII) in the manufacture of a combinatorial chemistry library or an array of compounds.
It will be appreciated by the skilled adressee that the solid supports which serve as the starting material will be loaded with an amount of linking agent comprising amide or sulphone functionalities which enables chemical synthesis of compounds of interest to proceed. Generally, the amount of linking agent to be loaded onto the resin can be any amount provided that the chemical synthesis of compounds of interest can proceed. Typically, the amount of a linking agent which may be loaded onto the resin can be any amount from 0.05 mmol/gram resin depending on the chemical synthesis contemplated. Generally, the amount of linking agent for loading onto the resin can be between 0.1 and 2.0 mmol/gram resin, more preferably between 0.25 and 1.25 mmol/gram resin and most preferably between 0.4 and 1.0 mmol/gram resin.